This invention relates to novel synthetic atrial peptides having useful natriuretic activity.
In recent years, considerable research investigation has been made on the atrial peptides. These are polypeptide hormones which were originally extracted from the heart atrial muscle. They have been denoted by various terminology such as cardionatrin, atrial natriuretic factor (ANF), atriopeptin (AP), atriopeptigen, auriculin and cardiodilatin. Biological activity has been shown with these peptides having amino acid chain lengths from as short as about 18 amino acids to as long as over 150 amino acids. The biological activity includes diuretic, natriuretic, smooth muscle relaxing, blood pressure lowering and other such properties having an important role in the regulation of volume balance, sodium homeotasis and vascular tone.
A great number of detailed articles have been published on the structure and biological properties of various of the atrial peptides. For brief background information on the atrial peptides in general, reference can be had to the following recent publications and the references cited therein:
Sagnella and MacGregor, Nature 309, 666-667 (1984); PA1 Palluk et al., Life Sci. 36 (15), 1415-1425 (1985); PA1 Needleman et al., Hypertension 7(4), 469-482 (1985); and PA1 de Bold, Science 230, 767-770 (1985). PA1 Ser-leu-arg-arg-AP-III and PA1 Arg-arg-AP-III. PA1 R.sub.1 =arg, arg-arg, leu-arg-arg, ser-leu-arg-arg, D-arg, D-arg-D-arg, PA1 R.sub.2 =OH, ser, ser-phe, ser-phe-arg, ser-phe-arg-tyr, and PA1 X=ile or met,
An important group of atrial peptides of significant interest, known as Atriopeptins I, II and III (AP-I, AP-II and AP-III), are described, for example, by Currie et al. Science 223, 67-69 (1984); Geller et al., Biochem. Biophys. Res. Commun. 120(2), 333-338 (1984); and Needleman, U.S. Pat. No. 4,496,544. These peptides in the oxidized (cyclized) form have the following amino acid sequences: ##STR1##
It is known that loss of the carboxy-terminal phe-arg from AP-II markedly suppresses the vasodilator activity whereas extension of the C-terminal phe-arg-tyr of AP-III does not enhance vascular reactivity. See Wakitani et al., J. Lab. Clin. Med. 105(3), 349-352 (1985).
Extensions of these peptides at the amino-terminal also are known, for example,
See Flynn et al., Biochem. Biophys. Res. Commun. 117(3), 859-865 (1983); and Seidah et al., Proc. Natl. Acad. Sci. USA 81, 2640-2644 (1984). Ser-leu-arg-arg-AP-III has been described as the major circulating form of atrial peptide. Schwartz et al., Science 229, 397-400 (1985).
Differential structure-activity relationships of these atrial peptides as natriuretics and renal vasodilators has been discussed, for example, by Thibault et al., Biochem. Biophys. Res. Commun. 125(3), 938-946 (1984); Garcia et al., Ibid. 126(1), 178-184 (1985); Katsube et al., Ibid. 128(1), 325-330 (1985); and Johnson, Life Sci. 38(3), 225-231 (1985).
As distinguished from the rat-derived atrial peptides, the human-derived analogs contain methionine instead of isoleucine in position number 8 in the above sequences for AP-I, II and III. See, for example, Kangawa et al., Biochem. Biophys. Res. Commun. 118(1), 131-139 (1984).